Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
The translocator protein (18 kDa) (TSPO), formerly known as the peripheral benzodiazepine receptor (PBR), can form a trimeric complex with the adenine nucleotide carrier (ANC) (30 kDa) and the voltage-dependent anion channel (VDAC) (32 kDa) to constitute the mitochondrial permeability transition pore (MPTP). The TSPO is distinguished from the central benzodiazepine receptor (CBR) by its distinct structure, physiological functions and subcellular location on the outer membrane of the mitochondria. Although the TSPO has been implicated in numerous biological processes, some aspects of its physiological role remain unclear. Studies implicate the TSPO in the rate limiting step of steroid biosynthesis, immunomodulation, porphyrin transport, calcium homeostasis, and programmed cell death.
The TSPO has been implicated in a variety of diseases, including: glioblastoma (Pappata et al., 1991 J Nucl Med 32:1608-10; Veenman et al., 2004 Biochem Pharmacol. 68(4):689-98; Levin, 2005 Biochemistry 44(29):9924-35), multiple sclerosis (Vowinckel et al., 1997 J Neurosci Res 50:345-53; Banati et al., 2000 Brain 123(Pt 11): 2321-37; Debruyne et al., 2003 Eur J Neurol 10: 257-64; Versijpt et al., 2005 Mult Scler 11:127-34; Chen and Guilarte, 2006 Toxicol Sci. 91(2):532-9), ischemic stroke (Gerhard et al., 2000 Neuroreport; 11:2957-60; Gerhard et al., 2005 Neuroimage 24:591-5; Price et al., 2006 Stroke 37:1749-53), herpes encephalitis (Cagnin et al., 2001 Brain; 124:2014-27), Parkinson's disease (Cumming et al., 2001. Acta Neurol Scand 103:309-15; Cicchetti et al., 2002 Eur J Neurosci 15:991-8; Ouchi et al., 2005 57:168-75; Gerhard et al., 2006 Neurobiol Dis 21:404-12; Cumming et al., 2006 Synapse 59:418-26), HIV (Venneti et al., 2004 J Clin Invest 113:981-9; Hammoud et al., 2005 J Neurovirol 11:346-55; Wiley et al., 2006 J Neurovirol 12:262-71), amyotrophic lateral sclerosis (Turner et al., 2004 Neurobiol Dis 15:601-9), corticobasal degeneration (Henkel et al., 2004 Mov Disord 19:817-21; Gerhard et al., 2004 Mov Disord 19:1221-6), Huntington's disease (Pavese et al., 2006 Neurology 66:1638-43), Cancer (Hardwick et al., 2002 Cancer Genet Cytogenet. 139(1):48-51; Papadopoulo V. 2003 Ann Pharm Fr. 61(1):30-50; Han Z., 2003 J Recept Signal Transduct Res. 23(2-3):225-38), Alzheimer's disease (Papadopoulo V. 2003 Ann Pharm Fr. 61(1):30-50; Li et al., 2007 Biochem Pharmaco. 73(4):491-503), depression (Gavioli E C., 2003 Eur J Pharmacol. 13; 471(1):21-6; Kita A. 2004 Br J. Pharmacol. 142(7):1059-72) and Cancer, auto-immune, infectious and neurodegenerative diseases (Galiegue et al., 2003 Curr Med Chem 10: 1563-72). It is widely acknowledged that ligands of the TSPO may be of benefit in the treatment of such diseases.
The TSPO is densely distributed in most peripheral organs including the lungs, heart and kidneys, yet it is only minimally expressed in the normal brain parenchyma. Following neuronal injury or infection, TSPO expression in the brain parenchyma is dramatically increased. In vitro autoradiography and immunohistochemistry has revealed that elevated TSPO binding in this region directly correlated with the appearance of activated microglia. Recently, in vivo positron emission tomography (PET) imaging in patients suffering from Alzheimer's disease (AD) and multiple sclerosis (MS) confirmed that TSPO binding in the brain parenchyma was confined to activated microglial cells.
Microglia are the principal immune effecter cells of the central nervous system (CNS). These macrophage-like immune cells are assumed to derive from monocytic lineage and their primary role lies in host defense and immune surveillance. They are highly sensitive to changes in their microenvironment and rapidly become activated in response to pathological events. For this reason, the TSPO is believed to be intimately associated with initial inflammatory processes in the early stages of several neurodegenerative disorders.
A number of classes of TSPO ligands have been reported over the past few decades including the benzodiazepines (diazepam and Ro 5-4864), isoquinoline carboxamides (PK 11195), indoleacetamides (FGIN-1-27), phenoxyphenyl-acetamides (DAA1106), pyrazolopyrimides (DPA-713), benzothiazepines and imidazopyridines. Some other classes have also been developed. However, a more extensive range of ligands with varying binding properties and biological activity is required to better characterise the physiological and therapeutic roles of TSPO, its exact localisation and the anticipated existence of TSPO subtypes.
The isoquinoline carboxamide [11C](R)-PK 11195 has been used as a pharmacological probe for studying the function and expression of TSPO. A number of PET studies conducted in patients with AD, MS and multiple system atrophy (MSA) has shown that measurement of TSPO in vivo with [11C](R)-PK 11195 is feasible in the living brain. Although [11C](R)-PK 11195 is regarded as the most widely used PET TSPO ligand it displays a poor signal to noise ratio and has demonstrated low brain permeability which ultimately decreases its sensitivity as a marker of microglial activation.
In 1998, the phenoxyphenyl-acetamide derivative, DAA1106, was reported as a highly selective and potent ligand for the TSPO (Chaki, S.; Funakoshi, T.; Yoshikawa, R.; Okuyama, S.; Okubo, T.; Nakazato, A.; Nagamine, M.; Tomisawa, K. European Journal of Pharmacology, 1999, 371, 197-204). DAA1106 has been labelled with carbon-11 (11C) and used in PET studies to evaluate its in vivo kinetics in both rodent and primate brains (Zhang M R, Kida T, Noguchi J et al. [11C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain. Nucl Med Biol 2003; 30:513-519. Maeda J, Suhara T, Zhang M R et al. Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET: An imaging tool for glial cells in the brain. Synpse. 2004; 52:283-291). The binding of [11C]DAA1106 was shown to be four times greater than [11C](R)-PK 11195 in the monkey occipital cortex, indicating its superior brain permeability. A fluorine-18 (18F) analogue of this compound has also been synthesised, namely [18F]FEDAA1106, and this analogue also displays similar binding characteristics in vivo to [11C]DAA1106 (Zhang M R, Maeda J, Ogawa M et al. Development of a new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl)acetamide, for PET imaging of peripheral benzodiazepine receptor in primate brain. J Med Chem. 2004; 47:2228-2235. The binding of both [11C]DAA1106 and [18F]FEDAA1106, however, appear to be irreversible and, in fact, their slow elimination from the brain indicates that they may not have suitable kinetics for quantitative analysis.
Ryu J K et al, Neurobiology of Disease, 20 (2005) 550-561 reports that the TSPO ligand PK 11195 reduces microglial activation and neuronal death in quinolinic acid-injected rat stratum. The results reported in this paper suggest that inflammatory responses from activated microglia are damaging to striatal neurons and thus pharmacological targeting of TSPO in microglia is likely to protect neurons in neurological disorders.
More recently in WO 2007/134362, the present Applicant has shown 2-arylpyrazolo(1,5-a]pyrimidin-3-yl acetamide derivatives as ligands, and in particular DPA-714, specifically bind to TSPO with high affinity.
International application WO 2008/022396 discloses fluorinated ligands for targeting peripheral benzodiazepine receptors.
It would be advantageous to identify TSPO ligands with improved brain kinetics that can be used to image TSPO expression in vivo, as such ligands could be utilised to further study the cascade of biochemical events involved in the initial stages of several neurodegenerative disorders. It would also be advantageous to identify TSPO ligands with improved brain kinetics as such ligands have potential to serve as both diagnostic and therapeutic tools for neurodegenerative disorders.
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
It is an object of the invention in its preferred form to provide compounds and methods for imaging translocator protein (18 kDa) (TSPO) expression in a subject. It is also an object of the invention in its preferred form to provide compounds and methods for the treatment of neurodegenerative disorders, inflammation or anxiety in a subject.